Trastuzumab-DM1 produced higher response rates with less toxicity than did a combination of trastuzumab and docetaxel in the first randomized trial of the novel agent as first-line therapy for metastatic HER2-positive breast cancer.
At a median six months’ follow-up, overall response rates were 48% in the trastuzumab-DM1 (T-DM1) arm and 41% in the trastuzumab (Herceptin) – docetaxel (Taxotere) arm of the open-label phase II trial. Three of 67 women treated with the novel drug had complete responses, compared with 1 of 70 women given trastuzumab and docetaxel.
Serious adverse events of grade 3 or higher in the T-DM1 arm were about half as frequent with T-DM1 as in the control arm (37% vs. 75%), but 1 treatment-related death was reported in the experimental arm. The most common adverse events were nausea, fatigue, and pyrexia in women treated with T-DM1.
Dr. Edith Perez of the Mayo Clinic in Jacksonville, Fla. will report the preliminary data Oct. 11 in Milan at the annual meeting of the European Society for Clinical Oncology. A professor of medicine at the Mayo Medical School, she is principal investigator of the ongoing study. A larger three-armed phase III trial called MARIANNE is comparing T-DM1 monotherapy to trastuzumab plus a taxane and to T-DM1 plus pertuzumab, which also targets HER2.
The U.S. Food and Drug Administration recently refused a request from Roche to fast-track T-DM1 based on positive single-arm studies. Although the women in those studies had been heavily pretreated, the agency said they had not exhausted all options.
T-DM1 combines two lines of attack in one agent: the anti-HER2 activity of trastuzumab, a monoclonal antibody, with the targeted intracellular delivery of DM1, a potent antimicrotubule agent. The DM1 component is licensed by ImmunoGen, Inc.
In a press statement, Dr. Fabrice André from Institut Gustave Roussy in Villejuif, France, described the results to be reported by Dr. Perez as important for two reasons.
“Firstly, they confirm that in coming years chemotherapy could be replaced by a less toxic compound .... These results suggest that, with the same efficacy, T-DM1 could dramatically reduce the toxicities related to chemotherapy."”
Secondly, Dr. André observed that the study offers proof of concept for the linking of a monoclonal antibody to a cytotoxic drug in an anti-cancer therapy. “This could have several implications beyond drugs that target HER2,” Dr André said.
Dr. Perez declared no conflicts of interest. Several of her coauthors disclosed receiving research support from Roche/Genentech and three identified themselves as employees and stockholders of Roche.
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一项随机研究表明，与联用曲妥珠单抗+多烯紫杉醇相比，新药曲妥珠单抗-DM1作为一线药物治疗转移性人表皮生长因子受体2(HER2)阳性乳腺癌的疗效更佳且毒性更小，这在同类研究中尚属首次。
在这项开放式Ⅱ期临床试验进行到中位随访时间6个月时，曲妥珠单抗-DM1(T-DM1)组患者的总缓解率为48%，曲妥珠单抗(赫赛汀)+多烯紫杉醇(Taxotere)联合用药组为41%。新药治疗组和联合用药组患者的完全缓解率分别为3/67和1/70。T-DM1组患者出现3级或更高级别严重不良事件的几率约为对照组的一半(37%对75%)，但试验组出现1例治疗相关的死亡。T-DM1组最常见的不良事件为恶心、乏力和发热。
法国维瑞勒夫Gustave Roussy 研究所的Fabrice André博士认为该研究具备两大重要意义：首先，该试验表明，在未来，研究者有望在维持化疗药物疗效的同时降低其毒性；其次，该研究对抗癌治疗中联用单克隆抗体和某种细胞毒药物进行了概念验证研究，今后将有望在其他领域应用该概念。
美国食品药品管理局(FDA)近期驳回了罗氏公司希望加速T-DM1审批进程的请求，因为该机构认为仍须对所有治疗方案进行全盘考虑。
本研究的主要研究者Edith Perez博士表示无利益冲突。其余几位共同作者披露接受了来自罗氏和基因泰克公司的研究经费支持，3位研究者表示他们是罗氏公司股东。
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